Quality Lab Stability MARCH 2018 Volume 42 Number 3

PLUS: Agreements Operations Testing

Early
Development
Strategies

PEER-REVIEWED
A New Method for Risk Assessment
of Pharmaceutical Excipients
PARTICLE ENGINEERING TOPICAL DRUG FORMULATION API SYNTHESIS & MANUFACTURING
Dry Particle Coating Products with Live Microorganisms Orphan Drug Development
 March 2018 Volume 42 Number 3

Pharmaceutical Technology is the authoritative source of peer-reviewed research

and expert analyses for scientists, engineers, and managers engaged in process
development, manufacturing, formulation and drug delivery, API synthesis, analytical
techno
tec
technology
hnolog
logg y and
and testing,
testin
tes ting,
g, packaging,
p kag
pac ging, IT, outsourcing, and regulatory compliance in the
pha
harma
rmaceu
rma ceutic
ceu
pharmaceuticaltical
tic al and biotechnology
biote
bi otechn
ote chnolo
chn o ogy
olo g y industries.
ind

COVER STORY
cover
ove r

18 Can Early Development

Strategies Avoid
he c

Later-Stage Disasters?
n tthe

Assessing potential formulation and manufacturing issues in early

development phases can improve a drug’s chances for success.
On

Cover Design by Dan Ward

Images: arbalet/Shutterstock.com
O

FEATURES
F E ATURES
API SYNTHESIS
S & MA
ANU
UFA
ACTURIN
NG QUA
ALIT
TY L AB OPERA
ATIONS

22 Small Volumes, 48 Good Quality 58 Improving

Big Challenges Agreements Support Operations in the Lab
Highly complex APIs developed to treat rare Compliance with CGMP   New and emerging products advance
and orphan diseases present big technical Drug manufacturers can improve bio/pharma laboratory operations.
questions for contract developers. use of quality agreements in
contract manufacturing. COLD CHA
AIN DIS
STR
RIBU
UTIO
ON
PART
TIC
CLE ENG
GINE
EER
RING
G

26 Dry Particle Coating— ANA

ALY
Y TICS
S 60 Poseidon Takes on the
Pharma Supply Chain
A Unique Solution for 52 Stability Testing Lower costs, fewer opportunities
Pharmaceutical Formulation Determines Proper
for temperature excursions, and a
Aston Particle Technologies has Drug Storage Parameters
smaller carbon footprint are making
developed a technology that produces Stability testing on APIs/finished drug ocean transport more attractive
functionalized particles in a one-step, product helps define optimal drug for pharmaceuticals. Poseidon, a
environmentally friendly process. packaging for shelf-life storage. new collaborative pharma initiative,
TOPICA
AL DRUG
G FO
ORM
MUL
L ATION
N seeks to leverage benefits.

32 Formulating Topical Continued on page 8

Products Containing
Live Microorganisms as
the Active Ingredient
Case studies compare efficacy
testing of preservatives for topical
formulations with probiotic actives.

PEER-REVIEWED RESEARCH SU
UPP
PLEM
MENT
Be sure to check out this month’s
PEE
ER-RE
EVIEW
WED
D special issue, Solid Dosage Drug Development
and Manufacturing, for articles on taste masking,
38 A New Method for Risk tablet development, nanoprecipitation, and more!
Assessment of Pharmaceutical Excipients
This article describes a new, combined, quantitative method for The issue also includes our
assessing excipient risks that has been developed by the authors. CPh
hI No
orth Ameerica 2018
8 Pla
annin
ng Gu
uide.

PharmTech.com
 Peer-Reviewed

A New Method for

Risk Assessment of
Pharmaceutical Excipients
Yurii Pidpruzhnykov, Olena Ruban, and Tetiana Kolisnyk

N
According to the modern requirements of the ormative requirements for finished medicine produc-
European Union’s Good Manufacturing Practice for tion are constantly being improved. These changes
Medicinal Products, a manufacturing authorization are associated with progress in science and technol-
ogy, improvement of control methods and engineer-
holder should guarantee the suitability of
ing support systems for manufacturing, development and
excipients included in the finished medicine. launch of next-generation drugs to the market, enhance-
For this purpose, a formalized, documented ment of the control systems for technological process and
assessment of risks associated with safety, quality, products, and the introduction of new pharmacopoeial and
and function for each excipient should be carried regulatory requirements, for example. The European Union
out. Though the EU-GMP guidelines give an good manufacturing practice (EU-GMP) requirements (1)
are meant to be mandatory rules in the field of pharmaceuti-
indicative list of parameters that should be taken
cal production, and the EU-GMP rules are amended almost
into consideration when assessing the excipient every year. These changes encompass both the structure
risks, none of the known and cited sources specifies and the content of the document, including modification of
how to perform such an assessment. The present the conceptual framework for GMP. The most recent GMP
article, therefore, describes a new, combined, changes were comprehensive (2).
quantitative method for assessing excipient risks In the new requirements of the EU-GMP Chapter 5, it
is noted that the level of supervision over starting material
that has been developed by the authors as one
manufacturers should be proportionate to the risks associ-
possible risk evaluation method. This method ated with particular types of starting materials, taking into
represents a combination of a quantitative risk account the source, production technology, supply chain,
assessment (based on the risk index method) and its use in the composition of a finished medicine (1).
and a qualitative risk ranking method. The risk The new regulation is focused on assuring the quality of the
components related to safety, quality, and function excipients that influence the quality of the finished phar-
maceuticals. Finished medicine manufacturers, therefore,
of excipients as well as parameters included in
should monitor manufacturers and suppliers of excipients.
them are considered, and the score points are For this purpose, it is necessary to use an approach based on
assigned to each excipient. The developed method a documented risk assessment, which is described in the new
was used for excipient risk assessment of some guidelines, adopted in 2015 (3) and entered into force in the
marketed finished medicines manufactured EU since March 21, 2016. In turn, these guidelines (3) have
MONA MAKELA/SHUTTERSTOCK.COM

by Ukrainian pharmaceutical enterprises. been developed and adopted in pursuance of the Directive of
the European Parliament and the EU Council 2011/62/EU (4),
which has made appropriate changes in the Directive 2003/81
(the primary regulation for the drug distribution chain) (5).
According to the normative documents (3–5), the manu-
facturing authorization holder (MAH) should guarantee the
suitability of excipients used in finished medicine manufac-
Submitted: Nov. 21, 2017 ture by determining an appropriate set of GMP requirements.
Accepted: Jan. 4, 2018 In turn, this set should be determined on the basis of a for-
38 Pharmaceutical Technology MARCH 2018 P h a r mTe c h . c o m
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 Peer-Reviewed
Table I: Instructions for assigning parameters and score points to the Safety (S) malized overall assessment of excipient
excipient risk component. risks. The task to guarantee the quality
of the excipients is quite complicated
Safety (S) Score
because the manufacturers of excipients
Spongiform encephalopathy: S1
mostly aren’t MAHs and are not covered
Raw materials of animal origin are used for the manufacture of excipient 1 by regulatory GMP-inspections. More-
Raw materials of animal origin are not used for the manufacture of excipient 3 over, such manufacturers may refuse to
Potential for viral contamination: S2 be audited by MAHs. Thus, one way a
Impossible 1 MAH can determine if an excipient is
Possible but not significant for this particular pharmaceutical form 2 of appropriate quality and can be used
Possible and significant for this particular pharmaceutical form 3
safely in finished drug manufacturing
is by doing a risk assessment.
Potential for microbiological or endotoxin/pyrogen contamination: S3
An overall risk assessment should
Excipient has a synthetic origin and is resistant to microbial contamination 1
take into account the requirements of
It is possible, but not significant for this particular pharmaceutical form 2 other relevant quality systems to deter-
It is possible and significant for this particular pharmaceutical form, 3 mine the origin and the intended use
in instance, raw materials of animal and/or vegetable origin are used
of the excipients, as well as previously
in the excipient manufacturing process or the excipient could serve
as a substrate and stimulate the growth of micro-organisms recorded cases of defects in their qual-
Potential for any impurity originating from the raw materials (e.g., aflatoxins or
ity. A system of an overall assessment
S4 and management of excipient risks is
pesticides):
Raw materials of vegetable origin are not used in the excipient manufacturing process 1
incorporated in the pharmaceutical
quality system of a finished medicine
Raw materials of vegetable origin are used in the excipient manufacturing process 3
manufacturer. All actions within ex-
Potential for any impurity generated as part of the process and carried over (e.g.,
S5 cipient risk assessments are docu-
residual solvents and catalysts):
mented and are subject to GMP inspec-
Low potential for such an impurity 1
tion. A risk management approach has
High potential for such an impurity 3
been implemented in pharmaceutical
Sterility assurance for excipients claimed to be sterile: S6 manufacturing for more than 10 years,
The excipient sterility is ensured 1 and methods and tools that can be
There are some problems with the excipient sterility ensuring 2 used in the risk management prosess
The excipient sterility is not ensured 3 are described in International Council
Potential for any impurities carried over from other processes, in absence of for Harmonization (ICH) Q9 (6). This
S7 list, however, is not exhaustive and
dedicated equipment and/or facilities:
Low potential for such impurities 1 could be expanded using other tools or
High potential for such impurities 3
combinations. Numerous examples of
risk assessment methods and tools are
described (7, 8), but information about
Figure 1: Low-, medium-, and high-risk areas (respectively, which approach is useful for excipient risk evaluation and
from left to right) derived from the risk components: safety (S), details of how this evaluation could be done are lacking.
quality (Q) and excipient function (F), expressed in score points This article, therefore, aims to provide such information.
from one to three. The guidelines (3) establish the fundamental principles
that should guide a finished medicine manufacturer in the
excipient risk assessment and note that the instruments
and methods described in ICH Q9 (6) can be used for this
purpose. The guidelines (3) provide an indicative list of
parameters that should be taken into consideration when
FIGURE IS COURTESY OF THE AUTHORS

assessing the excipient risks, but in the authors’ opinion, it

is not complete and the parameters included in a particular
risk component need more in-depth study and additional
individual assessment. In a previous publication (9), the
authors have considered the possible algorithms for the
risk assessment of excipient function in every particular
pharmaceutical formulation. The present work was aimed
at the development of a quantitative, combined method
for the overall risk assessment of excipients that can be
40 Pharmaceutical Technology MARCH 2018 P h a r mTe c h . c o m
applied by industrial pharmaceutical axes in three-dimensional space: Q, S, which can be designated by the letter
enterprises. and F (see Figure 1). The total risk index that corresponds to the component
(TRI) is calculated using Equation 1: name and the index that corresponds
Risk method development to the parameter number. For example,
The method developed by the authors TRI = S × Q × F [Eq. 1]. Q3 denotes the third parameter related
is a combination of a quantitative risk to the quality component, and F1 to F7
assessment based on the use of the risk For simplicity, a three-point scale denotes the parameters of the excipient
index method using scores (10) and a (from one to three) is used for each function component (see Tables I–III).
qualitative risk ranking method. The component. Each of these parameters is quantified
quantitative characteristic used in the In turn, each of these components from one to three points, and the risk
first stage ensures the objectivity of includes a number of parameters, value is calculated for the components
the assessment and a more accurate
characterization of the risk level. The
qualitative ranking method applied in
the second stage enables interpretation
and further practical use of such an as-
sessment. Applying the method using
Proven Innovation for
quantitative analysis of the risk com- Non-destructive Testing of
ponents and the parameters included
in them determines a risk category as Parenteral Packaging
low, medium, or high risk.
To develop this method, the following
tasks were performed:
• The components that affect the ex-
cipient risk and that can be consid-
ered as independent variables were
studied.
• A set of parameters within each
of the risk components was deter-
mined.
• A scoring system for the param-
eters, and accordingly for the risk
components, was established.
• An algorithm for the quantitative Data Driven
Robust Inspection
assessment of the risk components
was developed.
• Low-, medium-, and high-risk

Solutions
areas in the resulting three-di-
mensional space were determined.
• From the three-dimensional space
in the risk assessment, one can
move to a simpler and more un-
derstandable qualitative rank (low,
medium, or high risk).
• The developed method is tested
by assessing risk of commercial
excipients from Ukrainian phar-
maceutical enterprises.
E-

Ve
D

ca L y
S

nM HV riP ca
ic r o C u r re n t a c Va c u u m D e
The guideline (3) identifies quality (Q),
safety (S), and function (F) of excipients
in a finished medicine as the components
that affect excipient risk. Each of the risk PTI - Packaging Technologies and Inspection
914.337.2005 | www.ptiusa.com | Tuckahoe, New York
components for an individual excipient
is represented in the form of coordinate
Pharmaceutical Technology MARCH 2018 41
Peer-Reviewed
Table II: Instructions for assigning parameters and score points to the Quality With a chosen scale of one to three
(Q) excipient risk component. Parameters not included in guidelines (3) are in score points for each risk factor, the
italics. maximum total risk index will be equal
to 27, using Equation 1:
Quality (Q) Score
Control of transportation and storage conditions, including cold chain management: Q1
TRI = S × Q × F = 3 × 3 × 3 = 27
No cases of non-observance of established conditions 1
for transportation and storage upon delivery
The minimum possible risk will be
Only one case of non-observance of the conditions for 2
one, using Equation 1:
transportation and storage as delivered
More than one case of non-observance of conditions for 3
transportation and storage upon delivery
TRI = S × Q × F = 1 × 1 × 1 = 1
Supply chain complexity: Q2
Within the framework of this ap-
Direct supply chain from excipient manufacturer 1
proach, the risk indexes of each excipi-
Supply through one distributor 2 ent in each finished medicine are cat-
Supply through two or more intermediaries 3 egorized by Equations 2–4:
Stability of the excipient: Q3
No problems with stability of the excipient 1 Low risk: 1 ≤ TRI < 6 [Eq. 2]
Problems with stability of the excipient 3
Assurance of package integrity: Q4
Medium risk: 6 ≤ TRI <12 [Eq. 3]
No package defects or integrity failure have been identified 1
High risk: 12 ≤ TRI ≤ 27 [Eq. 4].
A few single cases of package defects have been identified 2
Multiple cases of significant package defects have been identified 3 Additional requirements may be used
Related to the excipient quality defects or adulterations, identified both globally and when assigning a category. For example,
Q5
at a local company level:* if the value of at least one of the com-
No defects and adulterations have been identified 1 ponents (S, Q, or F) is three, then the
Single defects have been identified 2 overall risk in any case cannot be attrib-
Adulterations have been identified 3 uted to a low risk area, but should be at-
Results of sterility input control for the excipient claimed to be sterile: Q6 tributed to the medium or high risk. It
At least one recorded case of a nonconformance of the excipient in this parameter 3
should also be understood that although
Figure 1 gives an idea of the risk areas in
Any excipient defects recorded during reported period, which were identified in the
Q7 the chosen three-dimensional space, it
input control:
A proportion of identified defects less than 1% 1
is rather simplistic, because in practice,
calculated values of risk components
A proportion of identified defects from 1% to 10% 2
will not be round numbers, but non-
A proportion of identified defects more than 10% 3
integral values, as described previously.
Results of input control for the critical quality attributes of the excipient (e.g., Defining component parameters.
Q8
identification, pyrogenicity, toxicity):
An important aspect of risk assessment
At least one recorded case of a nonconformance of the excipient 3 within the framework of this algorithm
Results of input control for significant quality attributes of the excipient (e.g., assay
Q9 is identifying the parameters that are in-
content, impurity content, microbiological purity): cluded in each of the risk components.
At least one recorded case of a nonconformance of the excipient in this parameter 3 Certainly, the choice of the main param-
*This parameter was included in F in the guidelines, but here is included in Q. eters should be guided by the norma-
tive document (3), but it insufficiently
S, Q, or F as the arithmetic mean of the parameters included defines which parameters are included
in each of the components. To decrease the error of the over- in each of the components. In addition, the normative docu-
all risk assessment, when calculating the arithmetic mean of ment does not contain a clear separation of the parameters
the parameters at the stage of component assessment, one included in the individual components of excipient risk. In
should not round the obtained values to whole numbers. the authors’ opinion, for some components, the listed param-
Rounding should be limited to the first significant digit eters should relate to another risk component. For example,
after the decimal point. By substituting such values into the following parameters are assigned to the functional char-
the formula (1), a more accurate assessment of the overall acteristic of excipients in the finished medicine (3):
risk index is obtained, and the resulting value is rounded • The pharmaceutical form and use of the finished medi-
to whole-number values at the final stage of the calculation. cine containing the excipient
42 Pharmaceutical Technology MARCH 2018 P h a r mTe c h . c o m
 • The excipient function in the fin- Table III: Instructions for assigning parameters and score points to the
ished medicine (examples are given) excipient function (F) risk component. Parameters not included in guidelines
• The proportion of the excipient in (3) are in italics.
the finished medicine composition
Excipient function (F) Score
• Daily patient intake of the excipient
Pharmaceutical form and use of the finished medicine containing the excipient: F1
• Any known excipient quality de-
fects/adulterations, both globally External (topical) administration 1

and at local company level Oral administration 2

• Whether the excipient is a mixture Sterile pharmaceutical product 3
• Known or potential impact on the Technological function of the excipient in the finished medicine composition
critical quality attributes of the fin- Functionality-related characteristics are absent in the F2
ished medicine European Pharmacopoeia (Ph.Eur.) monograph or are not significant
• Other factors affecting patient For this particular excipient function in the pharmaceutical form 1
safety. Not more than 2 functionality-related characteristics, described in the 2
In the authors’ opinion, a parameter Ph.Eur. monograph, are related to this particular excipient function

associated with defects of excipient Three or more functionality-related characteristics described in the 3
quality or adulterations refers not to Ph.Eur. monograph are related to this particular excipient function

a functional characteristic, but to the The proportion of the excipient in the finished medicine composition: F3
quality risk component (Q). Moreover, Proportion of the excipient does not exceed 10% 1
the parameters referred to the safety Proportion of the excipient is between 10% and 40% 2
and quality risk components in the Proportion of the excipient exceeds 40% 3
guidelines (3) are not separated and are Daily intake of the excipient administered with the finished medicine to a patient F4
given in one list. Understanding how
Up to 100 mg 1
these parameters relate to precisely
From 100 mg to 500 mg 2
those risk components is unclear, and
additional information is needed. To More than 500 mg 3

better define the F component, the au- Whether the excipient is a mixture: F5
thors used the approach of the European The excipient is not a mixture, but an individual substance 1
Pharmacopoeia (Ph.Eur.) Chapter 5.15 The excipient is a premixed blend of two individual substances 2
“Functionality-related characteristics of The excipient is a premixed blend of more than two substances 3
excipients” (11). Although this chapter The impact of the excipient (its function) on providing established biomedical
is not mandatory, it is useful in the au- F6
requirements to the finished medicine:
thors’ excipient risk assessment method. The excipient does not affect biomedical requirements 1
The authors also added several param-
The excipient function is directly linked to providing 3
eters to the Q component. biomedical requirements to the finished medicine
The final step in developing risk as- Known or potential impact of the excipient on the critical quality attributes of the
sessment algorithm was to determine F7
finished medicine:
what points (and in what cases) should The finished medicine meets specification criteria even when a 1
be assigned to each of the parameters proportion of the excipient is changed by ±50% of the nominal
included in each risk component. Tables The finished medicine meets specification criteria when a proportion of 2
I–III list the instructions and the point the excipient is changed by not more than ±25% of the nominal
values developed by the authors. The finished medicine meets specification criteria when a proportion of 3
the excipient is changed by not more than ±10% of the nominal

Table IV: The results of the risk assessment for the excipients included in the medicinal product “Insular Stabil”.
Excipients, included in the medicinal product Risk components Total risk index
No
composition S Q F (TRI)
1 Protamine sulfate 1.7 1.9 2.1 7
2 Di-Sodium hydrogen phosphate dehydrate 1.4 1.6 2.0 4
3 Glycerol 1.6 1.7 2.0 5
4 Meta-cresol 1.3 2.0 2.0 5
5 Phenol 1.3 1.6 2.0 4
6 Water for injections 1.4 1.3 2.1 4

Pharmaceutical Technology MARCH 2018 43

Peer-Reviewed
Method validation 2. Y. V. Podpruznikov and V.N. Shestakov, J. Drug Development &
Registration 3, 202-218 (2016).
Assessment of the authors’ method for the risk assessment
3. EC, Guidelines of 19 March 2015 on the formalised risk assessment
of excipients in finished medicines was carried out by four for ascertaining the appropriate good manufacturing practice for
Ukrainian manufacturers of finished medicines. At least excipients of medicinal products for human use (2015/С 95/02),
five specialists at each company participated. http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%
The risk assessment for excipients in a medicinal product 3A52015XC0321%2802%29, accessed 10 Nov 2017.
4. EU, Directive 2011/62/EU (2011).
(Insular Stabil) produced by one of these companies (Arte-
5. EU, Directive 2001/83/EC (2001).
rium) is presented in Table IV as an example. This medicinal 6. ICH, ICH Harmonised Tripartite Guideline: Quality Risk Manage-
product is produced in the form of a suspension for injec- ment Q9 (2005) International Conference on Harmonisation of
tion, in which 1 mL contains 100 IU of human recombinant Technical Requirements for Registration of Pharmaceuticals for
insulin. The authors’ method was used to obtain values of Human Use, www.ich.org/products/guidelines/quality/article/
quality-guidelines.html, accessed 10 Nov 2017.
the S, Q, and F risk components for each excipient (see Table
7. PDA, “Quality Risk Management for Aseptic Processes, Technical
IV). The TRI value of each excipient, listed in Table IV, was Report 44” PDA J. Pharm. Sci. and Technol. 68 (S-1) 1-43 (2008).
calculated according to Equation 1 using the values of the 8. PDA, Implementation of Quality Risk Management for Pharma-
parameters from Tables I–III. The arithmetic mean was cal- ceutical and Biotechnology Manufacturing Operations, Technical
culated and rounded to two significant digits. The TRI value Report No. 54. (Bethesda, MD, 2012).
9. O. Ruba, Y. Pidpruzhnykov, and T. Kolisnyk, J. Pharm. Investiga-
for each excipient was rounded at the end of the calculation.
tion DOI:10.1007/s40005-017-0354-4 (Aug. 16, 2017).
To transition from a quantitative assessment to a qualita- 10. ISO, ISO/IEC 31010:2009. Risk management — Risk assessment
tive rank, the authors used the inequalities in Equations 2–4. techniques (Geneva, 2009).
As shown in Table IV, only protamine sulphate is character- 11. European Pharmacopoeia 9.0, Chapter 5.15, “Functionality-re-
ized in expert assessments by an average risk level (i.e., the lated Characteristics of Excipients” (EDQM, Strasbourg, France,
2016) 753-754. PT
value is in the range of 6 < TRI < 12); other excipients have
a low risk level (i.e., TRI value < 6).
From this and similar assessments carried out at the other
companies, the authors found that only some of the excipi-
ents included in the corresponding finished medicines have
an average (medium) risk level. The overwhelming majority Additional Reading
of the examined excipients were of low risk, and none of Visit PharmTech.com to read the following:
them were of high risk.
• Managing Risk in a Complex Excipient Supply Chain
www.PharmTech.com/managing-risk-complex-excipient-supply-chain
Conclusion
A new method for assessing the risks of excipients in the fin- • The Real Complexity of Excipient Composition
ished medicine composition has been developed and can be www.PharmTech.com/real-complexity-excipient-composition
used as one of the possible methods for excipient risk evalu- • Characterization of Polymeric Excipients
ation. This method represents a quantitative assessment of www.PharmTech.com/characterization-polymeric-excipients
risks using the scoring system within the risk indexes with • Collaboration Key to Meeting Excipient GMP Requirements
subsequent ranking and transition to the final qualitative www.PharmTech.com/collaboration-key-meeting-excipient-gmp-requirements
assessment of the excipient risk level. The advantage of the
• Understanding How Excipients Affect Drug Quality
method is more objective quantitative evaluation that uses
www.PharmTech.com/understanding-how-excipients-affect-drug-quality-1
a comprehensive list of parameters. The authors’ method
has been introduced at one of the Ukrainian enterprises as • Dealing with Complexity in Excipients and Formulations
a component of the standard operating procedure for as- www.PharmTech.com/dealing-complexity-excipients-and-formulations
sessing the risks of excipients that are part of the finished • Excipients for Formulation Success
medicines produced by this enterprise. www.PharmTech.com/excipients-formulation-success
This work is the first stage in solving a more general task
of establishing an appropriate set of good manufacturing
practices requirements for excipients used in the manufac- Yurii Pidpruzhnykov is a professor of the Department
ture of finished medicines. The authors plan to publish fur- of Quality Management, Olena Ruban is a professor of
ther approaches to solving this broader problem. the Department of Industrial Technology of Drugs, and
Tetiana Kolisnyk* is a PhD student of the Department of
Industrial Technology of Drugs, all at the National University
References of Pharmacy, Kharkiv, Ukraine; Tel: 380682474033,
1. EC, EudraLex—The Rules Governing Medicinal Products in the
kolisnyktatyana@gmail.com.
European Union. Volume 4—Medicinal Products for Human and
Veterinary Use: Good Manufacturing Practice, https://ec.europa.
*To whom all correspondence should be addressed.
eu/health/documents/eudralex/vol-4_en, accessed 10 Nov 2017.

44 Pharmaceutical Technology MARCH 2018 P h a r mTe c h . c o m